Project Summary Magnetic hyperthermia is a highly promising therapeutic modality for treatment of various cancers. It is based on the concept that magnetic nanoparticles delivered to cancer tumors can generate heat after exposure to a non-invasive external alternating magnetic field (AMF). Many preclinical and clinical studies have validated the significant potential of nanoparticle-mediated hyperthermia to either kill cancer cells directly or enhance their susceptibility to radiation and chemotherapy. Despite its promising potential, magnetic hyperthermia is currently limited to treatment of localized and relatively accessible tumors, because the required therapeutic temperatures above 42 0C can only be achieved by direct intratumoral injection of conventional iron oxide nanoparticles. To realize the true potential of magnetic hyperthermia as a therapy for deep-seated primary and metastatic tumors, it is necessary to develop nanoparticles that can efficiently accumulate at tumor sites following systemic administration and generate desirable intratumoral temperatures upon exposure to AMF. A multidisciplinary team of investigators with complementary expertise in nanomedicine, magnetic hyperthermia, and cancer research will develop novel nanoparticles with high heating capacity that efficiently accumulate in primary and metastatic tumors following a single systemic injection and generate desirable intratumoral temperatures upon exposure to AMF. The research team will capitalize on its recent invention of magnetic nanoclusters consisting of hexagonal-shaped nanoheaters encapsulated in polymeric nanoparticles. Preliminary studies validated that these nanoclusters are safe, efficiently accumulate in subcutaneous cancer tumors after intravenous injection, elevate the intratumoral temperature to 44 0C in the presence of AMF, and significantly inhibit tumor growth. To advance this technology, the first major goal of this project is to optimize the developed nanoclusters for targeted delivery to ovarian and pancreatic cancer tumors by modifying their surface with the LHRH peptide. The second goal is to confirm, in rodents with metastatic ovarian cancer and orthotopic pancreas cancer, that the nanoclusters are efficient in increasing temperature of deep-seated primary and metastatic tumors. The third goal is to validate therapeutic efficacy of the nanocluster-mediated hyperthermia alone and in combination with chemotherapy in these animal models. These goals will be addressed with the following Specific Aims: 1. Optimize translational potential and tumor-targeted delivery of the developed nanoclusters. 2. Evaluate optimized magnetic nanoclusters in mice with human metastatic ovarian cancer. 3. Assess optimized magnetic nanoclusters in an orthotopic model of pancreatic cancer. At the completion of this project, the team expects to produce strong evidence that the optimized nanoclusters will efficiently accumulate in metastatic and deep-seated tumors following intravascular injection, produce the required intratumoral temperature, and significantly reduce the size of ovarian and pancreatic tumors. The long term goal is to develop a novel magnetic hyperthermia-based treatment for the tested tumors.